Congestive heart failure is a major cause of morbidity and mortality in the United States. While progress in conventional treatments is making steady and incremental gains to reduce heart failure mortality, there is a critical need to explore new therapeutic approaches. It is now apparent that gene therapy has broader potential in diseases such as congestive heart failure. Improvement in our understanding of the molecular mechanisms of heart failure, along with the development of novel and safer vectors for gene delivery, have led to the identification of novel targets that are difficult to manipulate pharmacologically but may be more amenable to gene therapy. In the last few years calcium cycling abnormalities and specifically deficiencies in sarcoplasmic reticulum calcium uptake have been hallmarks of advanced heart failure. The complex of SERCA2a-phospholamban-Protein phosphatase 1 has been difficult to target pharmacologically. However the encouraging results from the CUPID trial in which AAV1.SERCA2a gene transfer was found to be safe and demonstrated benefit in clinical outcomes has once again validated calcium cycling as being an important target for heart failure treatment. For this reason, I-1c with its additional benefits is emerging as an important and valid target for the treatment of heart failure. Even though AAV vectors have been shown to be safe in a number of trials including the CUPID trial, they have the following limitations when used in the setting of heart failure: 1) they are not specific for te heart and 2) pre-existence neutralizing antibodies to any individual serotype would result in the exclusion of a large percentage of the patients. In fact in the CUPID trial 50% of the screened heart failure patients had to be excluded because they had neutralizing antibody titers against AAV1. Nanocor Inc. has developed a chimeric of AAV that more specifically targets the heart and escapes the inherent immunity in patients. We have proposed to use these novel chimeric vectors, which are also known as Bio Nano Particles (BNP), to directly target I-1 in experimental models of heart failure. In the phase 1 part of this SBIR we demonstrated the efficacy of intracoronary delivery of BNP targeting I-1 in a porcine ischemic model of heart failure. In this phase 2 application, we will carry out dose-escalation efficacy study of BNP116.CMV.I1c by Intra-Coronary Infusion in a pre-clinical model of non-ischemic heart failure. This will validate our gene therapy approach in both ischemic and non-ischemic cardiomyopathies while allowing us to move forward towards an IND for the use of BNP116.CMV.I1c in a phase 1 trial.